The mitogenic effectors of isoproterenol in human hepatocellular carcinoma cells

Abstract

Abstract.Increasing data indicate that stress hormones and their corresponding receptors play an important role in the carcinogenesis and progression of hepatocellular carcinoma (HCC). However, there is presently no study investigating the influence of stress hormones in correlation with ß2-AR on human HCC cells. We examined the expression of ·1-and ß-ARs in human HCC cell line HepG2 and MHCC97H cells in comparison with that in human normal hepatic cell line HL-7702 cells (L-02), and the influence of isoproterenol (ISO) on the growth of these HCC cells using blocking agents in correlation with ß2-AR and its downstream signaling pathways. We found that ·1-AR was down-regulated and ß2-AR was up-regulated in HepG2 and MHCC97H cells. ISO dosedependently promoted the growth of both HepG2 and MHCC97H cells. ISO-induced growth and survival of HCC cells were effectively attenuated by ICI 118551, U0126 and PD153035, but not by H-89 or LY294002. ISO transiently activated MAPK/ERK1/2 in tumor cells which could be blocked either by ICI 118551 or U0126, but not by H-89, LY294002, or PD153035. These findings indicate that ISO mimicking a mitogen promoted the growth of HepG2 and MHCC97H cells via ß2-AR-mediated activation of both MAPK/ERK1/2 dependent and independent signaling pathways, and ISO activated MAPK/ERK1/2 by an EGFRindependent mechanism.

Cannabinoid Receptor Activation Correlates with the Proapoptotic Action of the β2-Adrenergic Agonist (R,R′)-4-Methoxy-1-Naphthylfenoterol in HepG2 Hepatocarcinoma Cells

“…2A). Yuan et al (2010) reported similar potency of isoproterenol toward HepG2 cell proliferation, where saturation was reached at 10 M of the ␤-AR agonist. The EC 50 value reported here for isoproterenol was 400-fold lower than that reported in U118 cells (Toll et al, 2011).…”

“…In the case of ␤ 2 -AR agonists, the effect seems to be through cAMP-dependent pathways and is subject to antagonism by ICI 118,551 (Carie and Sebti, 2007;Toll et al, 2011). However, ␤ 2 -AR agonism has also been shown to elicit growth and survival of several different cancer cell types (Sastry et al, 2007;Yuan et al, 2010), such as the isoproterenol-induced increase in HepG2 cell proliferation (Yuan et al, 2010).…”

“…We have also demonstrated that ␤ 2 -AR agonists such as Fen and isoproterenol exert antiproliferative effects in the human-derived 1321N1 astrocytoma cell line specifically through the cAMP-dependent pathway (Toll et al, 2011), whereas Yuan et al (2010) reported that isoproterenol dosedependently induced the growth of the human-derived HepG2 hepatocellular carcinoma cell line. This cell typespecific divergence on cell proliferation by ␤ 2 -AR agonists raises questions about whether there is cross-talk between ␤ 2 -AR and other receptor-linked signaling cascades.…”

“…Because of the coexpression of ␤ 2 -AR and CBRs and their impact on HepG2 cell proliferation Yuan et al, 2010), we assessed whether the regulation of mitogenesis in response to Fen and MNF could occur through CBR signaling mechanisms.…”

Activation of β-adrenergic receptor promotes cellular proliferation in human glioblastoma

“…The effect of β-AR activation is cell-specific as β 2 -AR antagonists and agonists have been demonstrated to attenuate cell growth. For example, β-ARs activation may promote cell proliferation of certain cancer cells including lung cancer cells (20), ovarian carcinoma (5), human hepatocellular carcinoma cells (30), pancreatic (31), prostate (32), gastric (33) and colorectal cancer cells (34). By contrast, several studies have demonstrated that the β-AR agonist ISO suppresses the proliferation of MDA-MB-231 human breast cancer cells (35,36).…”